Drosophila melanogaster, the common fruit fly, is an important non-mammalian model system for human development and health. The recent completion of the Drosophila genome sequence has clearly demonstrated that humans and flies have a great deal in common. For example, critical genes involved in reproduction, kidney function, fat cell function, and tumor suppression are common to both. We use many of the system strengths to study genes involved in normal and abnormal function. System strengths include a completed genome, DNA microarrays, transgenesis, an extensive collection of lines of insects showing abnormal development or disease resistance. Most importantly, Drosophila has a short life cycle that allows completion of multi-generation experiments in a matter of months, not years or decades. All of these system strengths make Drosophila a truly outstanding translational model that will significantly augment our understanding of normal and abnormal human development, and human health and disease. Our current work focuses on determination and differentiation of the female germline and on the homolog of the human multiple endocrine neoplasia type-1 (men1) locus. Our long-term goals are to: 1) identify the major regulatory genes, 2) determine how they are related in terms of a gene network and 3) understand in detail how regulatory gene products function. We are question oriented and take advantage of genetic, molecular, genomic, and biochemical techniques. The first developmental choice faced by germ cells in the majority of higher eukaryotes is oogenesis versus spermatogenesis, but very little is known about how this basic event is genetically encoded in any organism. We have chosen to study the developmental genetics of this germline sex determination process in the fruit fly, Drosophila melanogaster. We have directly shown that a key regulator, ovo, binds to and directs transcription of ovarian tumor via an unusual initiator and UAS binding mechanism. We are currently studying the regulation of ovo transcription by signals from the somatic gonad and sex chromsome karyotype. The human tumor suppressor encoded by multiple endocrine neoplasia type-1 is a novel "pioneer protein" with no obvious homology to known protein families. We are using the power of Drosophila genetics to identify and characterize genes in the men1 pathway. Initial cloning and characterization of wildtype transcription patterns is complete, we are now generating loss-of-function and gain-of-function alleles which will be useful for finding out what men1 does. Preliminary results place Drosophila men1 in the TGFbeta and JNK signalling pathways.